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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Alternative splicing variant of NRP/B promotes tumorigenesis of gastric cancer

  • Kim, Aram (Department of Biochemistry, Institution of Basic Medical Science, School of Medicine, CHA University) ;
  • Mok, Bo Ram (Department of Biochemistry, Institution of Basic Medical Science, School of Medicine, CHA University) ;
  • Hahn, Soojung (Department of Microbiology, Institution of Basic Medical Science, School of Medicine, CHA University) ;
  • Yoo, Jongman (Department of Microbiology, Institution of Basic Medical Science, School of Medicine, CHA University) ;
  • Kim, Dong Hyun (Department of Dermatology, Bundang CHA Medical Center, School of Medicine, CHA University) ;
  • Kim, Tae-Aug (Department of Biochemistry, Institution of Basic Medical Science, School of Medicine, CHA University)
  • Received : 2022.02.23
  • Accepted : 2022.05.10
  • Published : 2022.07.31
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Abstract

Gastrointestinal cancer is associated with a high mortality rate. Here, we report that the splice variant of NRP/B contributes to tumorigenic activity in highly malignant gastric cancer through dissociation from the tumor repressor, HDAC5. NRP/B mRNA expression is significantly higher in the human gastric cancer tissues than in the normal tissues. Further, high levels of both the NRP/B splice variant and Lgr5, but not the full-length protein, are found in highly tumorigenic gastric tumor cells, but not in non-tumorigenic cells. The loss of NRP/B markedly inhibits cell migration and invasion, which reduces tumor formation in vivo. Importantly, the inhibition of alternative splicing increases the levels of NRP/B-1 mRNA and protein in AGS cells. The ectopic expression of full-length NRP/B exhibits tumor-suppressive activity, whereas NRP/B-2 induces the noninvasive human gastric cancer cells tumorigenesis. The splice variant NRP/B-2 which loses the capacity to interact with tumor repressors promoted oncogenic activity, suggesting that the BTB/POZ domain in the N-terminus has a crucial role in the suppression of gastric cancer. Therefore, the regulation of alternative splicing of the NRP/B gene is a potential novel target for the treatment of gastrointestinal cancer.

Keywords

Acknowledgement

We appreciate Dr. Shalom Avraham for providing us with NRP/B antibodies (VD2, SY5). This study was supported by a grant from the South Korean government (MSIT) and the Ministry of Health & Welfare, Republic of Korea (Grant No. HR16C0002) to DHK.

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